DOCSLIB.ORG

Breast Cancer Risk Is Associated with the Genes Encoding the DNA Double-Strand Break Repair Mre11/Rad50/Nbs1 Complex

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Breast Cancer Risk Is Associated with the Genes Encoding the DNA Double-Strand Break Repair Mre11/Rad50/Nbs1 Complex 2024 Breast Cancer Risk Is Associated with the Genes Encoding the DNA Double-Strand Break Repair Mre11/Rad50/Nbs1 Complex Huan-Ming Hsu,1,2,3 Hui-Chun Wang,2 Sou-Tong Chen,6 Giu-Cheng Hsu,4 Chen-Yang Shen,2,5 and Jyh-Cherng Yu3 1Graduate Institute of Medical Sciences, National Defense Medical Center; 2Institute of Biomedical Sciences, Academia Sinica; Departments of 3Surgery and 4Radiology, Tri-Service General Hospital; 5Life Science Library, Academia Sinica, Taipei, Taiwan; and 6Department of Surgery, Changhua Christian Hospital, Changhua, Taiwan Abstract The evolutionarily conserved Mre11-Rad50-Nbs1 observations that (a) one single-nucleotide polymor- (MRN) complex, consisting of proteins encoded by phism in Nbs1 was significantly associated with breast the genes Mre11, Rad50, and Nbs1, was recently shown cancer risk, and a trend toward an increased risk of to play a crucial role in DNA double-strand break developing breastcancer was found in women harbor- (DSB) repair by recruiting the nuclear protein kinase ing a greater number of putative high-risk genotypes of ataxia telangiectasia mutated to DSB sites, leading to MRN genes (an adjusted odds ratio of 1.25 for each activation of this DNA repair network. Given the fact additional putative high-risk genotype; 95% confidence that carriers of defective mutation and polymorphic interval, 1.10-1.44); (b) this association between risk and variants of ataxia telangiectasia mutated are athigher the number of putative high-risk genotypes was risk of developing breastcancer, we hypothesizeda stronger and more significant in women thought to be role of the MRN genes in determining breast cancer more susceptible to estrogen, i.e., those with no history susceptibility. This hypothesis was examined both in a of full-term pregnancy, those older (z26 years of age) at case control study of 559 breast cancer patients and first full-term pregnancy, or those having had fewer 1,125 healthy women of single-nucleotide polymor- (<2) full-term pregnancies; the risk effect conferred by phisms in Mre11, Rad50, and Nbs1 and by the in vivo harboring a higher number of high-risk genotypes of detection of binding between Mre11 and BRCA1, MRN genes was more significantin women withouta encoded by the breast cancer susceptibility gene history of breast feeding; and (c) Mre11 and BRCA1 BRCA1. We were also interested in defining whether were shown to form a complex in vivo, and this any association between MRN genes and breast cancer interaction was increased by irradiation. This study was modified by reproductive risk factors reflecting the supports the role of the MRN pathway in breast cancer level of estrogen exposure or susceptibility to estrogen development, further strengthening the suggestion that exposure, as estrogen is known to initiate breast cancer mechanisms regulating DSB repair may play a mutator development due to its metabolites causing DSB role driving breastcancer pathogenesis. (Cancer formation. Support for the hypothesis came from the Epidemiol Biomarkers Prev 2007;16(10):2024–32) Introduction Double-strand breaks (DSB) are extremely cytotoxic specific partner proteins. Recently, the evolutionarily DNA lesions, and cells have therefore developed an conserved Mre11/Rad50/Nbs1 (MRN) complex was extensive array of responses that lead to damage repair, implicated in ATM recruitment to DSBs (6-8). This thus preventing cell death (1-4). The nuclear protein complex is involved in the initial processing of DSBs kinase ataxia telangiectasia mutated (ATM) is regarded due to its nuclease activity and DNA binding capability, as the primary activator of this network, and the which reside in the Mre11 protein and partially depend recruitment of ATM to DNA DSBs is thought to be the on the interaction of Mre11 with Rad50, which provides critical step in its activation and function (5). However, the energy source for the MRN complex (9, 10). However, although ATM has an affinity for DNA, this recruitment in terms of the protein required for ATM recruitment, has been suggested to require and to be facilitated by it has only recently been recognized that Nbs1 recruits activated ATM to sites of DNA damage, then promotes its phosphorylation and the triggering of subsequent Received 2/7/07; revised 7/18/07; accepted 7/27/07. steps in the DNA damage response (11). These results The costs of publication of this article were defrayed in part by the payment of page show that the MRN complex functions as a DNA DSB charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734solely to indicate this fact. sensor upstream of ATM signaling. However, this critical Requests for reprints: Chen-Yang Shen, Institute of Biomedical Sciences, Academia role of the complex in initiating DSBs repair does not Sinica, Taipei, 11529, Taiwan. Fax: 886-2-2782-3047. E-mail: [email protected] exclude its involvement in mechanisms downstream or Jyh-Cherng Yu, Departments of Surgery, Tri-Service General Hospital, Taipei, 11529, Taiwan. Phone: 886-2-8792-7191. E-mail: [email protected] of ATM signaling in the intra-S or G2-M cell cycle Copyright D 2007 American Association for Cancer Research. checkpoint in response to DNA damage, as suggested in doi:10.1158/1055-9965.EPI-07-0116 earlier studies (9, 10). These functional links between Cancer Epidemiol Biomarkers Prev 2007;16(10). October 2007 Downloaded from cebp.aacrjournals.org on September 26, 2021. © 2007 American Association for Cancer Research. Cancer Epidemiology, Biomarkers & Prevention 2025 ATM and the MRN complex help explain similarities in ing the effects of subtle genetic variations, such as single the clinical and cellular phenotypes associated with nucleotide polymorphisms (SNP). Furthermore, the deficiency of each of the genes encoding these proteins. use of a genetically homogenous population (i.e., the Hypomorphic mutations in Mre11 and Nbs1 result, Taiwanese population) reduces the chance of false respectively, in the human genetic instability disease, positives due to population stratification (25, 26). The ataxia-telangiectasia–like disorder, and Nijmegen break- present study included 559 female breast cancer patients age syndrome (10, 12, 13). These single-gene disorders and 1,125 healthy female controls. All subjects gave their overlap with one another and with ataxia-telangiectasia, informed consent. The recruitment of both cases and caused by ATM deficiency, all being characterized by controls and considerations regarding methodologic neurologic abnormalities, radiosensitivity, impairment of issues (such as study design, sampling scheme, and the cellular response to DSBs, and genomic instability. potential bias) have been described and addressed in The close relationship between ATM and the MRN detail previously (16, 19, 20, 25, 26). complex prompted us to hypothesize a role of the MRN Questionnaire. Two experienced research nurses were genes in determining breast cancer susceptibility. The assigned to administer a structured questionnaire to both rationale underlying this hypothesis is that carriers cases and controls. The information collected and the of either defective mutations or polymorphic variants validity of this questionnaire have been addressed and of ATM are at higher risk of developing breast cancer confirmed in our previous studies (16, 19, 20, 25, 26). (14, 15). Furthermore, we have adopted a model (i.e., the hide-then-hit hypothesis; ref. 16) to explain the lack of Genotyping. Genomic DNA was extracted from the cancer predisposition in ataxia-telangiectasia–like disor- buffy coat isolated from whole-blood samples using a der patients or no breast cancer phenotype observed in QIAamp DNA extraction kit (Qiagen, Inc.) following the manufacturer’s protocol. Nijmegen breakage syndrome patients and suggest that a 7 disparate spectrum of disease phenotypes can be Using the current data from HapMap on haplotype differently caused by mutated forms or hypomorphic/ blocks of MRN genes in the Chinese population, we polymorphic variants of the same genes. This is because, selected SNPs in each block to detect genetic variation in in contrast to common genetic diseases, cancer formation these three candidate genes and five SNPs were selected requires an extended period of time for the essential for each MRN gene. These SNPs were chosen because genomic changes to accumulate. Genetic variants or low- they are evenly distributed throughout the entire genes, penetrance alleles of DNA repair genes (such as Mre11/ a total of 15 SNPs being genotyped (Mre11: rs535801, RAD50/NBS1 examined in the present study) may rs569143, rs601391, rs684507, and rs1061945; Nbs1: therefore have a chance to escape the lethality phenotype rs1805794, rs1805790, rs709816, rs1061302, and by not triggering obvious cell cycle surveillance, and the rs1063045; Rad50: rs2252775, rs2301713, rs3798134, cells accumulate the necessary genomic instability rs2240032, and rs2244012). Because there have not been leading to cancer development. In addition, the possibil- any reports of an association between genotypic and ity of manifesting the tumorigenic phenotype depends phenotypic changes in the SNPs of the MRN genes, these not only on the joint effect of individual genes but also on selected SNPs were used as markers to reflect possible the interaction between genes and risk factors. To test linkage disequilibrium (LD) between themselves and this hypothesis, we did this investigation based (a)on different alleles of a gene of unidentified phenotypic a case control study to estimate the breast cancer risk variation. We used more than one SNP per gene to have associated with harboring putative high-risk genotypes an unbiased definition of the allelic and haplotypic of MRN genes, (b) on an examination of the joint effect statuses of each gene. of MRN genotypes and well-established risk factors of All SNPs were genotyped using a MassARRAY breast cancer in determining cancer risk, and (c)onan (SEQUENOM, Inc.). The PCR primers and extension in vivo study of the interaction between MRN and BRCA1, primers for all SNPs were designed using Spectro- encoded by the breast cancer susceptibility gene BRCA1.
Load more

Recommended publications
  • The Functions of DNA Damage Factor RNF8 in the Pathogenesis And
    Int. J. Biol. Sci. 2019, Vol. 15 909 Ivyspring International Publisher International Journal of Biological Sciences 2019; 15(5): 909-918. doi: 10.7150/ijbs.31972 Review The Functions of DNA Damage Factor RNF8 in the Pathogenesis and Progression of Cancer Tingting Zhou 1, Fei Yi 1, Zhuo Wang 1, Qiqiang Guo 1, Jingwei Liu 1, Ning Bai 1, Xiaoman Li 1, Xiang Dong 1, Ling Ren 2, Liu Cao 1, Xiaoyu Song 1 1. Institute of Translational Medicine, China Medical University; Key Laboratory of Medical Cell Biology, Ministry of Education; Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, Shenyang, Liaoning Province, China 2. Department of Anus and Intestine Surgery, First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China Corresponding authors: Xiaoyu Song, e-mail: [email protected] and Liu Cao, e-mail: [email protected]. Key Laboratory of Medical Cell Biology, Ministry of Education; Institute of Translational Medicine, China Medical University; Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, Shenyang, Liaoning Province, 110122, China. Tel: +86 24 31939636, Fax: +86 24 31939636. © Ivyspring International Publisher. This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions. Received: 2018.12.03; Accepted: 2019.02.08; Published: 2019.03.09 Abstract The really interesting new gene (RING) finger protein 8 (RNF8) is a central factor in DNA double strand break (DSB) signal transduction.
    [Show full text]
  • 2. the MRN Complex
    reviewreview The MRN complex: coordinating and mediating the response to broken chromosomes Michael van den Bosch, Ronan T.Bree & Noel F. Lowndes+ Genome Stability Laboratory, National University of Ireland, Galway, Ireland The MRE11–RAD50–NBS1 (MRN) protein complex has been linked mechanisms by modification and activation of specific repair factors. to many DNA metabolic events that involve DNA double-stranded Alternatively, if the damage is irreparable or an excessive number of breaks (DSBs). In vertebrate cells, all three components are encoded lesions is present, checkpoint signalling is also required to induce by essential genes, and hypomorphic mutations in any of the human apoptotic cell death. The two main mechanisms of DSB repair are genes can result in genome-instability syndromes. MRN is one of the non-homologous end joining (NHEJ) and homologous recombination first factors to be localized to the DNA lesion, where it might initially (HR; Barnes, 2001; van den Bosch et al., 2002). The malfunction have a structural role by tethering together, and therefore stabiliz- of these mechanisms can result in the fusion of DNA ends that were ing, broken chromosomes. This suggests that MRN could function as originally distant from one another in the genome, which generates a lesion-specific sensor. As well as binding to DNA, MRN has other chromosomal rearrangements such as inversions, translocations and roles in both the processing and assembly of large macromolecular deletions. The resulting disruption of gene expression can perturb complexes (known as foci) that facilitate efficient DSB responses. normal cell proliferation or result in cell death. Recently, a novel mediator protein, mediator of DNA damage checkpoint protein 1 (MDC1), was shown to co-immunoprecipitate The MRN complex and the repair of DNA damage with the MRN complex and regulate MRE11 foci formation.
    [Show full text]
  • BASC, a Super Complex of BRCA1-Associated Proteins Involved in the Recognition and Repair of Aberrant DNA Structures
    Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures Yi Wang,1,2,6 David Cortez,1,3,6 Parvin Yazdi,1,2 Norma Neff,5 Stephen J. Elledge,1,3,4 and Jun Qin1,2,7 1Verna and Mars McLean Department of Biochemistry and Molecular Biology, 2Department of Cellular and Molecular Biology, 3Howard Hughes Medical Institute, and 4Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030 USA; 5Laboratory of Molecular Genetics, New York Blood Center, New York, New York 10021 USA We report the identities of the members of a group of proteins that associate with BRCA1 to form a large complex that we have named BASC (BRCA1-associated genome surveillance complex). This complex includes tumor suppressors and DNA damage repair proteins MSH2, MSH6, MLH1, ATM, BLM, and the RAD50–MRE11–NBS1 protein complex. In addition, DNA replication factor C (RFC), a protein complex that facilitates the loading of PCNA onto DNA, is also part of BASC. We find that BRCA1, the BLM helicase, and the RAD50–MRE11–NBS1 complex colocalize to large nuclear foci that contain PCNA when cells are treated with agents that interfere with DNA synthesis. The association of BRCA1 with MSH2 and MSH6, which are required for transcription-coupled repair, provides a possible explanation for the role of BRCA1 in this pathway. Strikingly, all members of this complex have roles in recognition of abnormal DNA structures or damaged DNA, suggesting that BASC may serve as a sensor for DNA damage.
    [Show full text]
  • ABSTRACT Title of Document: the FUNCTION of MRN (MRE11-RAD50- NBS1) COMPLEX DURING WRN (WERNER) FACILITATED ATM (ATAXIA- TELANGI
    ABSTRACT Title of Document: THE FUNCTION OF MRN (MRE11-RAD50- NBS1) COMPLEX DURING WRN (WERNER) FACILITATED ATM (ATAXIA- TELANGIECTASIA MUTATED) ACTIVATION Junhao Ma, Master of Science, 2009 Directed By: Assistant Professor, Dr. Wen-Hsing Cheng, Department of Nutrition and Food Science WRN (Werner) protein is a member of the RecQ family showing helicase and exonuclease activity. WRN protein may lose function upon mutation and causes Werner syndrome (WS) which is an autosomal recessive, cancer-prone and premature aging disease. ATM (Ataxia-Telangiectasia mutated) protein initiates a signaling pathway in response to DNA double strand breaks (DSBs). Genomic disorder ataxia- telangiectasia (A-T) is associated with defective ATM. WRN protein is involved in ATM pathway activation when cells are exposed to DSBs associated with replication fork collapse. Because the Mre11-Rad50-Nbs1 (MRN) complex, a sensor of DSBs, is known to interact with WRN and ATM, we investigated whether the MRN complex mediates the WRN-dependent ATM pathway activation. In this study, we employed short-hairpin RNA to generate WRN- and Nbs1-deficient U-2 OS (osteosarcoma) cells. Cells were treated with clastogens which induce collapsed replication forks, thus provided proof for whether WRN facilitates ATM activation via MRN complex. This study serves as a basis for future investigation on the correlation between ATM, MRN complex and WRN, which will ultimately help understand the mechanism of aging and cancer. THE FUNCTION OF MRN (MRE11-RAD50-NBS1) COMPLEX DURING WRN (WERNER) FACILITATED ATM (ATAXIA-TELANGIECTASIA MUTATED) ACTIVATION By Junhao Ma Thesis submitted to the Faculty of the Graduate School of the University of Maryland, College Park, in partial fulfillment of the requirements for the degree of Master of Science 2009 Advisory Committee: Professor Wen-Hsing Cheng, Chair Professor Mickey Parish Professor Liangli (Lucy) Yu © Copyright by Junhao Ma 2009 Dedication To my daughter Aimi, my wife Yangming, my father and mother.
    [Show full text]
  • Genome Instability and Rad50s: Subtle Yet Severe
    Downloaded from genesdev.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press PERSPECTIVE Genome instability and Rad50S: subtle yet severe Martijn de Jager1 and Roland Kanaar1,2,3 1Department of Cell Biology & Genetics, Erasmus MC, and 2Department of Radiation Oncology, Erasmus MC–Daniel, 3000 DR Rotterdam, The Netherlands In the early 1980s, a primary hurdle on the track to un- Rad50S/S mice derstanding the function of a protein was the isolation of To derive a viable mouse Rad50 allele, Bender et al. its gene. Over the last two decades, we have seen subse- (2002) took their clues from genetic analyses of the quent hurdles in the race to decipher protein function, RAD50 gene from the yeast Saccharomyces cerevisiae. including atomic structure resolution and the creation of RAD50-deficient S.cerevisiae cells are viable but display viable mouse mutants, being cleared at an ever-increas- mitotic and meiotic phenotypes. The cells are sensitive ing pace. The genome surveillance protein Rad50has to the DNA-damaging agent methyl methanesulfonate now leapt over these modern-day hurdles. In the last two (MMS) and are defective in the formation of viable years, rapid progress has been made in understanding spores. Alani et al. (1990) had isolated separation-of- structural aspects of Rad50 (Hopfner et al. 2000, 2001, function (rad50S) alleles of RAD50 that conferred no 2002; de Jager et al. 2001). In this issue of Genes & De- overt MMS sensitivity to the cells, but still blocked vi- velopment, John Petrini and colleagues report on the able spore formation. All of the nine different muta- phenotypes of mice carrying a hypomorphic Rad50 allele tions that resulted in the rad50S phenotype mapped named Rad50S (Bender et al.
    [Show full text]
  • DNA Repair with Its Consequences (E.G
    Cell Science at a Glance 515 DNA repair with its consequences (e.g. tolerance and pathways each require a number of apoptosis) as well as direct correction of proteins. By contrast, O-alkylated bases, Oliver Fleck* and Olaf Nielsen* the damage by DNA repair mechanisms, such as O6-methylguanine can be Department of Genetics, Institute of Molecular which may require activation of repaired by the action of a single protein, Biology, University of Copenhagen, Øster checkpoint pathways. There are various O6-methylguanine-DNA Farimagsgade 2A, DK-1353 Copenhagen K, Denmark forms of DNA damage, such as base methyltransferase (MGMT). MGMT *Authors for correspondence (e-mail: modifications, strand breaks, crosslinks removes the alkyl group in a suicide fl[email protected]; [email protected]) and mismatches. There are also reaction by transfer to one of its cysteine numerous DNA repair pathways. Each residues. Photolyases are able to split Journal of Cell Science 117, 515-517 repair pathway is directed to specific Published by The Company of Biologists 2004 covalent bonds of pyrimidine dimers doi:10.1242/jcs.00952 types of damage, and a given type of produced by UV radiation. They bind to damage can be targeted by several a UV lesion in a light-independent Organisms are permanently exposed to pathways. Major DNA repair pathways process, but require light (350-450 nm) endogenous and exogenous agents that are mismatch repair (MMR), nucleotide as an energy source for repair. Another damage DNA. If not repaired, such excision repair (NER), base excision NER-independent pathway that can damage can result in mutations, diseases repair (BER), homologous recombi- remove UV-induced damage, UVER, is and cell death.
    [Show full text]
  • Suppression of DNA-Damage Checkpoint Signaling by Rsk-Mediated Phosphorylation of Mre11
    Suppression of DNA-damage checkpoint signaling by Rsk-mediated phosphorylation of Mre11 Chen Chen, Liguo Zhang, Nai-Jia Huang, Bofu Huang, and Sally Kornbluth1 Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710 Edited by Tony Hunter, The Salk Institute for Biological Studies, La Jolla, CA, and approved November 12, 2013 (received for review April 9, 2013) Ataxia telangiectasia mutant (ATM) is an S/T-Q–directed kinase A hallmark of cancer cells is their ability to override cell-cycle that is critical for the cellular response to double-stranded breaks checkpoints, including the DSB checkpoint, which arrests the cell (DSBs) in DNA. Following DNA damage, ATM is activated and cycle to allow adequate time for damage repair. Previous studies recruited by the MRN protein complex [meiotic recombination 11 have implicated the MAPK pathway in inhibition of DNA-dam- (Mre11)/DNA repair protein Rad50/Nijmegen breakage syndrome age signaling: PKC suppresses DSB-induced G2/M checkpoint 1 proteins] to sites of DNA damage where ATM phosphorylates signaling following ionizing radiation via activation of ERK1/2 multiple substrates to trigger cell-cycle arrest. In cancer cells, this (22); activation of RAF kinase, leading to activation of MEK/ regulation may be faulty, and cell division may proceed even in ERK/Rsk, also can suppress G2/M checkpoint signaling (23). the presence of damaged DNA. We show here that the ribosomal Given its prominent role in multiple cancers, the MAPK s6 kinase (Rsk), often elevated in cancers, can suppress DSB-induced pathway is an attractive therapeutic target. Indeed, treatment of melanoma using the RAF inhibitor vemurafenib has shown some ATM activation in both Xenopus egg extracts and human tumor cell clinical success, as has treatment of nonsmall cell lung carcinoma lines.
    [Show full text]
  • Abnormal Function of Telomere Protein TRF2 Induces Cell Mutation and the Effects of Environmental Tumor‑Promoting Factors (Review)
    ONCOLOGY REPORTS 46: 184, 2021 Abnormal function of telomere protein TRF2 induces cell mutation and the effects of environmental tumor‑promoting factors (Review) ZHENGYI WANG1‑3 and XIAOYING WU4 1Good Clinical Practice Center, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610071; 2Institute of Laboratory Animals of Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital; 3Yinglongwan Laboratory Animal Research Institute, Zhonghe Community, High‑Tech Zone, Chengdu, Sichuan 610212; 4Ministry of Education and Training, Chengdu Second People's Hospital, Chengdu, Sichuan 610000, P.R. China Received March 24, 2021; Accepted June 14, 2021 DOI: 10.3892/or.2021.8135 Abstract. Recent studies have found that somatic gene muta‑ microenvironment, and maintains the stemness characteris‑ tions and environmental tumor‑promoting factors are both tics of tumor cells. TRF2 levels are abnormally elevated by a indispensable for tumor formation. Telomeric repeat‑binding variety of tumor control proteins, which are more conducive factor (TRF)2 is the core component of the telomere shelterin to the protection of telomeres and the survival of tumor cells. complex, which plays an important role in chromosome In brief, the various regulatory mechanisms which tumor cells stability and the maintenance of normal cell physiological rely on to survive are organically integrated around TRF2, states. In recent years, TRF2 and its role in tumor forma‑ forming a regulatory network, which is conducive to the tion have gradually become a research hot topic, which has optimization of the survival direction of heterogeneous tumor promoted in‑depth discussions into tumorigenesis and treat‑ cells, and promotes their survival and adaptability.
    [Show full text]
  • Lessons Learned from BRCA1 and BRCA2
    Oncogene (2000) 19, 6159 ± 6175 ã 2000 Macmillan Publishers Ltd All rights reserved 0950 ± 9232/00 $15.00 www.nature.com/onc Lessons learned from BRCA1 and BRCA2 Lei Zheng1, Shang Li1, Thomas G Boyer1 and Wen-Hwa Lee*,1 1Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, 15355 Lambda Drive, San Antonio, Texas, TX 78245, USA BRCA1 and BRCA2 are breast cancer susceptibility susceptibility genes has provided two human genetic genes. Mutations within BRCA1 and BRCA1 are models for studies of breast cancer. responsible for most familial breast cancer cases. To understand how the loss of BRCA1 or BRCA2 Targeted deletion of Brca1 or Brca2 in mice has function leads to breast cancer formation, mouse revealed an essential function for their encoded products, genetic models for BRCA1 or BRCA2 mutations have BRCA1 and BRCA2, in cell proliferation during been established. This work has revealed that Brca1 embryogenesis. Mouse models established from condi- homozygous deletions are lethal at early embryonic tional expression of mutant Brca1 alleles develop days (E)5.5 ± 13.5 (Gowen et al., 1996; Hakem et al., mammary gland tumors, providing compelling evidence 1996; Liu et al., 1996; Ludwig et al., 1997). Three that BRCA1 functions as a breast cancer suppressor. independent groups generated distinct mutations within Human cancer cells and mouse cells de®cient in BRCA1 Brca1, yet nonetheless observed similar embryonic or BRCA2 exhibit radiation hypersensitivity and phenotypes, including defects in both gastrulation and chromosomal abnormalities, thus revealing a potential cellular proliferation, and death at E6.5 (Hakem et al., role for both BRCA1 and BRCA2 in the maintenance of 1996; Liu et al., 1996; Ludwig et al., 1997).
    [Show full text]
  • Epigenetic Regulation of DNA Repair Genes and Implications for Tumor Therapy ⁎ ⁎ Markus Christmann , Bernd Kaina
    Mutation Research-Reviews in Mutation Research xxx (xxxx) xxx–xxx Contents lists available at ScienceDirect Mutation Research-Reviews in Mutation Research journal homepage: www.elsevier.com/locate/mutrev Review Epigenetic regulation of DNA repair genes and implications for tumor therapy ⁎ ⁎ Markus Christmann , Bernd Kaina Department of Toxicology, University of Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany ARTICLE INFO ABSTRACT Keywords: DNA repair represents the first barrier against genotoxic stress causing metabolic changes, inflammation and DNA repair cancer. Besides its role in preventing cancer, DNA repair needs also to be considered during cancer treatment Genotoxic stress with radiation and DNA damaging drugs as it impacts therapy outcome. The DNA repair capacity is mainly Epigenetic silencing governed by the expression level of repair genes. Alterations in the expression of repair genes can occur due to tumor formation mutations in their coding or promoter region, changes in the expression of transcription factors activating or Cancer therapy repressing these genes, and/or epigenetic factors changing histone modifications and CpG promoter methylation MGMT Promoter methylation or demethylation levels. In this review we provide an overview on the epigenetic regulation of DNA repair genes. GADD45 We summarize the mechanisms underlying CpG methylation and demethylation, with de novo methyl- TET transferases and DNA repair involved in gain and loss of CpG methylation, respectively. We discuss the role of p53 components of the DNA damage response, p53, PARP-1 and GADD45a on the regulation of the DNA (cytosine-5)- methyltransferase DNMT1, the key enzyme responsible for gene silencing. We stress the relevance of epigenetic silencing of DNA repair genes for tumor formation and tumor therapy.
    [Show full text]
  • Post-Translational Modification of MRE11: Its Implication in DDR And
    G C A T T A C G G C A T genes Review Post-Translational Modification of MRE11: Its Implication in DDR and Diseases Ruiqing Lu 1,† , Han Zhang 2,† , Yi-Nan Jiang 1, Zhao-Qi Wang 3,4, Litao Sun 5,* and Zhong-Wei Zhou 1,* 1 School of Medicine, Sun Yat-Sen University, Shenzhen 518107, China; [email protected] (R.L.); [email protected] (Y.-N.J.) 2 Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College; Kunming 650118, China; [email protected] 3 Leibniz Institute on Aging–Fritz Lipmann Institute (FLI), 07745 Jena, Germany; zhao-qi.wang@leibniz-fli.de 4 Faculty of Biological Sciences, Friedrich-Schiller-University of Jena, 07745 Jena, Germany 5 School of Public Health (Shenzhen), Sun Yat-Sen University, Shenzhen 518107, China * Correspondence: [email protected] (L.S.); [email protected] (Z.-W.Z.) † These authors contributed equally to this work. Abstract: Maintaining genomic stability is vital for cells as well as individual organisms. The meiotic recombination-related gene MRE11 (meiotic recombination 11) is essential for preserving genomic stability through its important roles in the resection of broken DNA ends, DNA damage response (DDR), DNA double-strand breaks (DSBs) repair, and telomere maintenance. The post-translational modifications (PTMs), such as phosphorylation, ubiquitination, and methylation, regulate directly the function of MRE11 and endow MRE11 with capabilities to respond to cellular processes in promptly, precisely, and with more diversified manners. Here in this paper, we focus primarily on the PTMs of MRE11 and their roles in DNA response and repair, maintenance of genomic stability, as well as their Citation: Lu, R.; Zhang, H.; Jiang, association with diseases such as cancer.
    [Show full text]
  • SV40 Large T-Antigen Disturbs the Formation of Nuclear DNA-Repair Foci Containing MRE11
    Oncogene (2002) 21, 4873 – 4878 ª 2002 Nature Publishing Group All rights reserved 0950 – 9232/02 $25.00 www.nature.com/onc REVIEW SV40 large T-antigen disturbs the formation of nuclear DNA-repair foci containing MRE11 Martin Digweed*,1, Ilja Demuth1, Susanne Rothe1, Regina Scholz2, Andreas Jordan2, Carsten Gro¨ tzinger3, Detlev Schindler4, Markus Grompe5 and Karl Sperling1 1Institut fu¨r Humangenetik, Charite´ – Campus Virchow-Klinikum, Humboldt Universita¨t zu Berlin, Germany; 2Klinik fu¨r Strahlenheilkunde, Charite´ – Campus Virchow-Klinikum, Humboldt Universita¨t zu Berlin, Germany; 3Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charite´ – Campus Virchow-Klinikum, Humboldt Universita¨t zu Berlin, Germany; 4Institut fu¨r Humangenetik, Theodor-Boveri-Institut fu¨r Biowissenschaften (Biozentrum), Bayerische Julius-Maximilians- Universita¨tWu¨rzburg, Germany; 5Department of Molecular and Medical Genetics, Oregon Health Sciences University, Portland, Oregon, USA The accumulation of DNA repair proteins at the sites of Keywords: ionizing irradiation; Fanconi anaemia; im- DNA damage can be visualized in mutagenized cells at mortalization the single cell level as discrete nuclear foci by immunofluorescent staining. Formation of nuclear foci in irradiated human fibroblasts, as detected by antibodies directed against the DNA repair protein MRE11, is Introduction significantly disturbed by the presence of the viral oncogene, SV40 large T-antigen. The attenuation of foci The two major mechanisms for DNA double strand formation was found in both T-antigen immortalized break (DSB) repair in mammalian cells are nonhomo- cells and in cells transiently expressing T-antigen, logous end joining (NHEJ) and homologous indicating that it is not attributable to secondary recombination (HR). Many genes involved in these mutations but to T-antigen expression itself.
    [Show full text]